Despite recent advances in antiviral therapy, there is no permanent cure for AIDS or HIV infection. Drug therapy, is a promising arena of investigation in terms of providing effective therapy, however because of side effects, compliance, and expense, progress has not been rapid. Compounding these difficulties is the fact that the availability of such drugs is limited in developing countries where it is estimated that 90% of HIV infections will occur by the year 2000.
Due to the success that vaccines to infectious diseases have had, the most noteable being against small pox and polio, the search for an effective vaccine against AIDS continues. A variety of approaches have been tried. Indeed, most HIV-1 vaccine development has concentrated on subunit vaccines. The difficulty with the subunit vaccine approach has been the ability to produce optimal immunity. At present, it is not known exactly which components of the HIV antigen(s) and the immune system are necessary for protection from natural infection.
Early vaccine trials have looked at recombinant subunit protein based immunogens, such as the HIV-1 envelope protein gp120. The results from this approach have been disappointing, although, immunization regimens that employ both live recombinant virus and subunit protein have, in some individuals, elicited both envelope specific CD8+ CTL and neutralizing antibody to the HIV-1 envelope (Cooney E L, et al., Proc Natl Acad Sci USA 1993; 90; 1882–86; McElrath M J, et al. J Infect Dis. 169: 41–47 (1994); Graham B S, et al. J Infect Dis 166: 244–52 (1992); and Graham B S, et al. J Infect Dis 167: 533–37 (1993)).
Studies of the envelop glycoprotein of HIV have not yielded a plausible path to vaccine development. For example, in respect of HIV-1 gp120, the signal sequence of HIV-1 envelop glycoprotein gp120, which is referred to as NSS for HIV-1 natural signal sequence, has been found to be associated with the extent of secretion of gp120. In this respect it has been shown that substitution of the NSS with either mellitin or IL-3 signal sequence renders a high level production and efficient secretion of gp120 (Li, Y., et al. Virology 204: 266–278 (1994); and Li, Y., et al. Proc. Natl. Acad. Sci 0.93: 9606–9611 (1996). However, it is not known whether the signal sequence of HIV-1 gp120 has a role to play in the pathogenicity of the virus.
The preferred route is the use of whole, inactivated virus vaccines, such as inactivated polio virus vaccine, or attenuated live virus vaccines, such as oral polio vaccine. Unfortunately, this approach in the search for an AIDS virus vaccine appears too dangerous, given the potential for problems such as the “Cutter incident” in which inadequate inactivation of the polio vaccine resulted in actual clinical polio. A previous approach has incorporated use of the wild-type HIV-1, however, it was impossible to produce an adequate amount of virus for killed whole virus because the yield of HIV-1 infected T-cell lines was very low (Coffin et al. Retroviruses, CSH Press, 1989). Assuming it is possible to increase yield, there is also concern about the potential liability in growing large volumes of infectious HIV-1.
With respect to HIV vaccines it is known that deletion of the HIV nef gene attenuates the virus. Desrosiers and his associates have demonstrated that vaccination of macaques with nef-deleted SIV protected wild-type SIV challenge (Daniels, M. D. et al. Science 258:1938 (1992); Desrosiers, R. C., et al. Proc. Natl. Acad. Sci. USA 86:6353 (1989)) and others have demonstrated that nef gene is dispensable for SIV and HIV replication (Daniels, M. D. et al. Science 258:1938 (1992); Gibbs, J. S., et al. AIDS Res. and Human Retroviruses 10:343 (1994); Igarashi, T., et al. J. Gen. Virol. 78:985 (1997); Kestler III, H. W., et al. Cell 65:651 (1991)). Furthermore, deletion of nef gene renders the virus to be non-pathogenic in the normally susceptible host (Daniels, M. D. e t al. Science 258:1938 (1992)). Although this deletion does not provide a form of the virus which is possible to produce in large quantities. Neither too, has this form of the virus been shown to be safe for the production of a vaccine.
Consequently, what is needed is a vaccine which is avirulent as well as being capable of being produced in large quantities, and without the previous concerns and problems of using wild-type HIV-1.